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Review Article | DOI: https://doi.org/10.31579/2693-2156/035
* Professor of Physiology and Medicine, Nabanji Medical Centre, P. O. Box 30243, Lusaka, ZAMBIA.
*Corresponding Author: Nightingale Syabbalo, Professor of Physiology and Medicine, Nabanji Medical Centre, P. O. Box 30243, Lusaka, ZAMBIA.
Citation: Nightingale Syabbalo, (2022). Aerosol Biologics for the Treatment of Eosinophilic Asthma. J Thoracic Disease and Cardiothoracic Surgery, 3(1); DOI:10.31579/2693-2156/035
Copyright: © 2022, Nightingale Syabbalo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 25 December 2021 | Accepted: 07 January 2022 | Published: 15 January 2022
Keywords: eosinophilic asthma; interleukins; biologics; tezepelumab; CSJ117
Asthma is a heterogeneous chronic airway disease comprising of distinct phenotypes characterized by different immunopathophysiologic pathways, clinical features, disease severity, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed cellularity, and paucigranulocytic asthma. Eosinophilic asthma is principally a T helper type 2 (Th2)-mediated airway disease. However, several other immune and structural cells secrete the cytokines implicated in the pathogenesis of eosinophilic asthma. Innate type 2 lymphoid cells, mast cells, basophils, and eosinophils secrete Th2 cytokines, such as interleukin-4 (IL-4), IL-13, and IL-5. Additionally, airway epithelial cells produce alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Alarmins are the key initiators of allergic inflammation at the sentinel mucosal surfaces. Innovative biotherapeutic research has led to the discovery of monoclonal antibodies which target and inhibit the immunopathological effects of the cytokines involved in the pathogenesis of eosinophilic asthma. Parenteral biologics targeting the inciting interleukins, include mepolizumab and reslizumab (anti-IL-5), benralizumab (anti-IL-5Rα), dupilumab (anti-4Rα), and tezelizumab (anti-TSLP). They have been shown to significantly reduce annualized exacerbation rates, improve asthma control, lung function, and quality of life. Currently, there are no pulmonary delivered aerosol biologics for topical treatment of asthma. CSJ117 is a potent neutralizing antibody Fab fragment against TSLP, formulated as a PulmoSol TM engineered powder, and is delivered to the lungs by a dry powder inhaler. Phase 2 placebo-controlled clinical trial evaluated the efficacy and safety of CSJ117. CSJ117 delivered as an inhaler attenuated the late asthmatic response (LAR), and the early asthmatic response (EAR) after allergen inhalation challenge (AIC) at day 84 of treatment. The maximum decrease in FVE1 from pre-AIC were significantly lower in the CSJ117 group compared to placebo (P = 029), during LAR. CSJ117 also significantly reduced fractional exhaled nitric oxide before AIC at day 83; and significantly reduced the allergen-induced increase in % sputum eosinophil count. Pulmonary delivery of biologics directly to the airway mucosal surface has several advantages over parenteral routes, particularly in treating airway diseases such as asthma. Inhaler delivered biologics, such as CSJ117 are innovative and attractive methods of future precision treatment of asthma, and other respiratory diseases.
Asthma is a significant public health, and socio-economical problem affecting more than 358 million individuals worldwide [1]. It is a heterogeneous chronic airway disease encompassing distinct phenotypes characterized by different immunopathophysiological pathways, clinical features, disease severity, physiology, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed cellularity, and paucigranulocytic asthma. Eosinophilic asthma is principally a T helper type 2 (Th2)-mediated disease. However, several other immune, such as innate type 2 lymphoid cells (ILC2s), mast cells, basophils, and eosinophils; and structural cells, including fibroblasts, myofibroblasts, and airway smooth muscle cells also secrete the cytokines, and chemokines implicated in the pathogenesis of eosinophilic asthma. Dysfunctional and injured airway epithelial cells exude a special type of cytokines termed alarmins, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Alarmins are the key initiators of allergic eosinophilic inflammation at the sentinel mucosal surfaces. Because there are several types of immune, and structural cells secreting cytokines promoting eosinophilic inflammation, eosinophilic asthma is also termed as Th2-high asthma, in contrast to Th2-low neutrophilic, and paucigranulocytic asthma.
Despite national guidelines [1-3], and innovative therapies, such as single dual inhaler or single triple inhaler therapy [4-7], about 3.6-10% of the patients with asthma are unresponsive to the standard of care therapy [8-10]. Precise understanding of the pathophysiological mechanisms, and pathways involved in the pathogenesis of asthma has led to the innovate discovery of biologics for add-on treatment of severe, uncontrolled eosinophilic asthma.
A repertoire of biologics are currently available for the treatment of severe, uncontrolled eosinophilic asthma [11-15].
Parenteral administered biologics targeting the inciting interleukins in the pathogenesis of asthma, include omalizumab (anti-IgE), mepolizumab and reslizumab (anti-IL-5), benralizumab (anti-IL-5Rα), dupilumab (anti-4Rα), and tezelizumab (anti-TSLP). However, monoclonal antibodies (mAb) are less effective in the treatment of other phenotypes of asthma with low blood eosinophil counts, and low fractional exhaled nitric oxide (FeNO) levels, such as neutrophilic, and paucigranulocytic asthma [16-19]. Moreover, omalizumab [20], mepolizumab and benralizumab [21], and dupilumab [22, 23] therapies reduce exacerbations by about 50%, and are unable to eliminate exacerbations completely. Discontinuation of the biologics may result in poor asthma control, and even worse symptoms, and frequent exacerbations. Thus, there is still unmet need to explore for novel biologics capable of treating most of the phenotypes of asthma, and to prevent airway remodeling, and fixed severe airflow limitation. (Table 1) depicts the dosages of the approved biologics for the treatment of severe eosinophilic asthma.
Biologic | Dosage | Efficacy |
Omalizumab* | 75-375 mg SC Q 2/4 wk | Reduces exacerbations (47-53%) |
Mepolizumab* | 100 mg SC Q 4 wk | Reduces exacerbations (50-60%) |
Reslizumab | 3 mg/kg IV Q 4 wk | Reduces exacerbations (34-75%) |
Benralizumab* | 30 mg SC Q 8 wk | Reduces exacerbations (25-60%) |
Dupilumab* | 300 mg SC Q 2 wk | Reduces exacerbations (60-80%) |
Tezepelumab* | 210 mg SC Q 4 wk | Reduces exacerbations (41-56%) |
Abbreviations: IV, intravenous, given over 25-50 min; SC, subcutaneous, Q, every; wk, weeks. * Approved for childhood asthma. Pediatric dosages depend on age and body weight of the child or adolescent.
Table 1: Dosages of approved biologics by the Food and Drug Administration for the treatment of severe asthma
Airway epithelial cells play a key role in the regulation of tissue homeostasis by producing and secreting several proteins, such as antioxidants, lipid mediators, cytokines, chemokines, and growth factors [24, 25]. Damaged, and dysfunctional epithelium produce large quantities of cytokines, and growth factors that interact with the underlying mesenchymal cells, including fibroblasts, and myofiblobasts to induce epithelial-mesenchymal transition (EMT), promote airway remodeling [26-28], resulting in persistent airway obstruction [26].
The epithelial-derived cytokines (also termed alarmins), such as interleukin-25 (IL-25) [29-31], IL-33 [31-34], and thymic stromal lymphopoietin (TSLP) [31,35-38] play an initiating key role in the pathogenesis of eosinophilic asthma. Alarmin cytokine secretion can be aroused by respiratory viral, bacterial, and fungal infections, allergens, proteases, chemical irritants, mechanical injury, and cytokines, such as TNF-α, IL-1β [24,29]. Epithelial-derived cytokines secretion during viral respiratory infections is the major trigger of asthma exacerbations, particularly in children [39,40].
Biologics targeting alarmin cytokines have a potential to prevent, and efficaciously treat asthma, and exacerbations [41-45]. Inhibiting upstream alarmin cytokines by specific monoclonal antibodies is a very effective strategy capable of interfering with the downstream inflammatory cascades resulting in eosinophilic asthma [41,46]. Current biologics are not disease modifying, and discontinuing treatment with these biologics result in return of the severity of asthma to pre-treatment levels, or even worsening of asthma control [47,48]. Blocking alarmins, has the potential to inhibit EMT, airway hyperresponsiveness, and remodeling, thus preventing decline in lung function, and persistent severe eosinophilic asthma [42].
Currently, there are no biologics targeting IL-25, and IL-33 approved for the treatment of eosinophilic asthma. Itepekimab is a human IgG4P monoclonal antibody targeting IL-33. Wechsler et al. [49] have shown that a single subcutaneous injection of itepekimab 300 mg reduces exacerbations, and improve asthma control, lung function (FEV1), and health-related quality of life (HLQoL). The efficacy of itepekimab was almost similar to that achieved by dupilumab, although the outcomes were slightly less. However, dual itepekimab plus dupilumab treatment did not result in any clinical and statistical improvement in asthma control, and lung function.
Tezepelumab is a first-in class fully-human IgG2ʎ monoclonal antibody that binds to TSLP, thus blocking its interaction with the TSLP heterodimeric receptor, TSLPR, henceforth inhibiting multiple downstream inflammatory pathways [50,51]. Tezepelumab administered as add-on therapy has been shown to be efficacious, safe, and well tolerated by patients with severe uncontrolled asthma, regardless of the phenotype of asthma. Several clinical trials have documented that tezepelumab significantly reduces exacerbations by about 71%, and improve asthma control, lung function [52,53], and HLQoL in patients with severe, uncontrolled asthma [52]. Subgroup analysis of the PATHWAY study revealed that the reductions in annualized asthma exacerbation rates (AAER) were significant irrespective of patient phenotype, as assessed by blood eosinophil count (˂ 150 cells/µL), ≥ 150 cells/µL, < 300>
Pham et al. [54] re-analysis of the PATHWAY data showed that tezepelumab reduced blood eosinophil count, serum IgE, and FeNO levels; and Th2 cytokines, including IL-5, and IL-13 in patients with severe, uncontrolled asthma. Based on the findings from the PATHWAY studies, tezepelumab was granted Breakthrough Therapy Designation by the US Food and Drug Administration (FDA) in 2019 for patients with severe asthma without an eosinophilic phenotype, who were receiving ICS/LABA with or without OCS, and additional asthma controllers [55].
Phase III NAVIGATOR multi-centre, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of tezepelumab in 1061 patients aged 12 to 80 years with severe, uncontrolled asthma [56]. Tezepelumab significantly reduced the annualized asthma exacerbation rate by more than half in this broad group of patients (P ˂ 0.001). The AAER average was 0.9 in the 529 patients who received tezepelumab versus 2.10 for the 532 patients who received placebo in the 52 week trial. Tezepelumab also significantly improved lung function. Pre-bronchodilator FEV1 improved from baseline by about 0.23 L on average with tezepelumab, and by a mean of 0.09 L in patients who received placebo (P ˂ 0.001). Furthermore, tezepelumab treatment reduced the rate of emergency department visits by fivefold, and hospitalization by 85%. Notably, there was significant improvement in the Asthma Control Questionnaire-6 (ACQ-6), and the Asthma Quality of Life Questionnaire (AQLQ) scores [56]. This shows that tezepelumab is efficacious and safe for the treatment of adolescents and adults with severe, uncontrolled asthma.
Post-hoc analysis of phase 2b PATHWAY multicentre, randomized, double-blind, placebo-controlled study of 555 patients aged 18-75 years with severe, uncontrolled asthma with or without nasal polyps (NP) revealed that tezepelumab reduced AAER in both groups of patients [57]. Patients who received placebo with asthma and NP, and asthma without NP had higher AAER compared to those treated with tezepelumab [56]. The AAER was reduced to a similar extent in both groups of patients with asthma and NP, and asthma without NP who received tezepelumab 210 mg. The reduction in AAER for patients with asthma and NP was 75%, and the reduction in AAER was 73% in patients with asthma without NP. In both groups of patients who received placebo, patients experienced one to three more exacerbations than in the tezepelumab 210 mg group. Furthermore, treatment with tezepelumab 210 mg resulted in decrease in blood eosinophil counts, and FeNO levels compared to placebo [57].
Exploratory analysis of the NAVIGATOR phase III trial has demonstrated that tezepelumab reduced exacerbations, and improved lung function; and nasal symptoms in patients with severe, uncontrolled asthma with nasal polyps [58]. Tezepelumab reduced AAER by 86% in patients with asthma and nasal polyposis, and by 52% in patients with asthma without nasal polyposis over 52 weeks, compared to placebo. Tezepelumab improved lung function at week 52 in both groups of patients with an increase in pre-bronchodilator FEV1 of 0.20 L in the patients with asthma and NP, and 0.13 L in patients with asthma without NP. Concomitantly, tezepelumab significantly improved symptoms of nasal polyps at week 52. It significantly reduced the SinoNasal Outcome Test (SNOT-22, [59]) scores in patients with asthma and nasal polyps by 9.6 points versus placebo. The adjusted mean scores reduction from baseline for tezepelumab was 20.10 points, and for placebo was 10.55 points. The baseline mean (± sd) SNOT-22 scores for tezepelumab was 49.4 ± 21.5, and for placebo was 47.8 ± 19.0 [56]. Thus, demonstrating that tezepelumab may also be effective in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) [58]. Tezepelumab is in phase 3 clinical trials for the treatment of CRSwNP.
The results from the NAVIGATOR trial exploratory analysis are exciting [58]. Patients with eosinophilic asthma and comorbid chronic rhinosinusitis with nasal polyps have more severe united airway disease than patients with eosinophilic asthma or CRSwNP alone [57,60]. Asthmatic patients with CRSwNP experience frequent exacerbations, hospitalization, emergency department visits; and have poor lung function, and HLQoL [61,62]. On the other hand, patients with CRSwNP and asthma have persistent severe nasal obstruction, hyposmia, sleep disturbance, anxiety, and depression, and worse HLQoL [63-65]. They are often corticosteroid dependent, and require frequent functional endoscopic nasal surgery for nasal polyps [66,67].
Treatment of severe eosinophilic asthma with comorbid CRSwNP is challenging. Such patients require a universal targeted therapy, such as biologics, and in particular biologics delivered directly to the nasal airways, and tracheobronchial tree. Currently, there are no approved intranasal or inhaler biologics for the treatment of eosinophilic asthma, and CRSwNP. Noteworthy, dupilumab [68], and omalizumab [69] which are administered subcutaneously are approved for the treatment of both eosinophilic asthma, and CRSwNP.
Pulmonary Delivery of Aerosol Biologics
Biological drugs (synonymous known as biologics) are a diverse group of therapeutic agents which are large and complex molecules produced through sophisticated biotechnology [70, 72]. The biologics currently used to treat severe asthma are monoclonal antibodies, and antibody fragments, which are administered subcutaneously, or intravenously (reslizumab). Injection of drugs is painful and inconvenient, especially when the drugs are for the treatment of chronic diseases, such as asthma, and alpha-1 antitrypsin deficiency [73, 74]. Moreover, 10% of the patients worldwide suffer from needle phobia leading to poor compliance [75]. Pulmonary delivery of biologics to the lungs improve pharmacokinetics, and toxicity profiles of proteins. It is a non-invasive route, and allows for self-administration, which could improve patient compliance [76].
Pulmonary delivery of biologics is an attractive non-invasive route of administration for the treatment of respiratory diseases [76-79], such as asthma [80-84], cystic fibrosis [85, 86], alpha-1 antitrypsin deficiency (AATP) [87,88], pulmonary alveolar proteinosis (PAP) [89,90], lung cancer [91,92], and SARS-CoV-2 [93-95]. Pulmonary delivery of biologics is also an alternative route for administering biologics for the treatment of non-respiratory systemic diseases, including diabetes mellitus [96-98], anaemia [99], and multiple sclerosis [100]. The development of inhalation biologics, and design of methods of inhalation technology are outside the scope of this manuscript, but excellent information can be found in references [76-79]. Table 2 shows preclinical trials of aerosol biologics for the treatment of respiratory diseases, and non-respiratory systemic diseases.
Alpha-1 anti-trypsin deficiency (AATP) Pulmonary alveolar proteinosis (PAP) Cystic fibrosis Bronchiectasis Bronchiolitis obliterans organizing pneumonia (BOOP) Asthma Chronic obstructive pulmonary disease (COPD) Acute aplastic bronchitis Pulmonary hypertension Respiratory viral infections (RSV, Parainfluenza) Pneumonia (Pseudomonas aeroginosa) Tuberculosis Non-tuberculous mycobacterial infection Acute lung injury (ALI) Acute respiratory distress syndrome (ARDS) Respiratory viral infections (RSV, influenza) SARS-CoV-2 Lung cancer, lung metastasis Diabetes mellitus Multiple sclerosis Anaemia Infertility |
Table 2: Preclinical trials of aerosol biologics in respiratory diseases, and non-respiratory systemic diseases
The large surface area, and the extensive vascularization of the airways, and lungs enable rapid absorption, and fast onset of action of drugs delivered to the lungs [101]. Pulmonary delivery also offers the advantage of delivering biologics at high concentration in the lungs, and directly to inflammatory cells, and has the potential to achieve high blood levels of the biologics. Additionally, there is a lower level of proteolytic enzymatic activity in the lung, and minimal first-pass metabolism [76], hence higher concentrations of the biologics in the airways, and lung parenchyma.
However, despite the beneficial effects of pulmonary delivery of biologics, it requires innovative biotechnology to develop biologics, and inhaler devices to propel the biologics to the tracheobronchial tree, and lung parenchyma [76-79]. Furthermore, there are anatomical, physiological, and immunological factors that affect the pharmacodynamics, and biotherapeutic efficacy, and safety of inhaled biologics [102]. The other obstacle is the formulation of biologics for delivery into the lungs [78,79, 103]. Three methods have been applied to modify the structure, aerodynamic diameter (Dae), shape, hydroscopicity, and density of biologics to enhance their absorption through the mucociliary blanket, pharmacokinetics, and bioavailability [104,105]. They include antibody fragment development [106,107], Fc engineering [108,109], and pegylation [110,111]. Pegylation protects proteins from renal clearance and proteolytic degradation, thus prolongs protein local residence time, and bioavailability in the body [110]. Pegylation has been shown to be an effective method for extending the retention time of biologics in the lung, such as human alpha-1 proteinase inhibitor (α1-PI) [112], IFN-α [113], and antibody fragments [114,115].
The type of inhaler has critical importance for the delivery of biologics, because 75% of inhaled protein formulations in clinical research are produced as liquids [76]. There are four main types of inhalers for the delivery of orally inhaled proteins, peptides, and cytokines, such as pressure metered dose inhalers (PMDI), dry powder inhalers (DPI), soft mist inhalers (SMI), and nebulizers [77,79,116-120].
Most biologics in clinical trial for the treatment of asthma have been delivered to the lung by DPIs. However, SMIs are novel multidose propellant-free, handheld inhalers, and are more suitable for delivery of biologics than pMDI [79]. The most experience of pulmonary delivery of biologics with DPIs has been the Exubera® and Technosphere® insulin (Afrezza®), for the treatment of diabetes mellitus [121]. Currently, three DPIs have been utilized in clinical trials for the delivery of biologics to the lungs. They include the F1P for administration of the anti-IL-13 monoclonal antibody fragment VR942 (Abrezekimab) [102]; Cyclohaler® (single dose, PB Pharma GmbH, Meerbusch, German) for the administration of DAS181 (Fludase®) [122]; and Concept1 (single dose, Norvatis, Basel, Switzerland) (NCT4410523) for administration of the anti-thymic stromal lymphopoietin monoclonal antibody Fab fragment CSJ117 [84,123]. Biotechnological modification of proteins and peptides, and proper inhaler devices can be successfully used to deliver biologics which are effective, and immunologically safe for the treatment of airway diseases, pulmonary diseases, and systemic diseases.
The precise mechanism by which mAb, and antibody fragments exert their immunotherapeutic effects is by inhibiting surface receptors on immune and inflammatory, and immune cells, thus preventing these cells from secreting cytokines, chemokines, and adhesion molecules. Several mAb, and antibody fragments are currently in preclinical and clinical trials for the treatment of eosinophilic asthma [81-83,120,122-126], and neutrophilic asthma [127]. However, CSJ117 has demonstrated very encouraging and promising results.
Csj117 Dpi for the Treatment of Eosinophilic Asthma CSJ117 is a potent neutralizing antibody Fab fragment against TSLP. It is formulated as a PulmoSol TM engineered powder in hard capsules for delivery to the lungs by a dry powder inhale (DPI). Phase 2 double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of CSJ117 on the late asthmatic response (LAR), the early asthmatic response (EAR), and biomarkers of eosinophilic asthma after allergen inhalation challenge (AIC) [84,128]. CSJ117 significantly attenuated the LAR and EAR at day 84 of treatment. The maximum decrease in FVE1 from pre-AIC were significantly lower in the CSJ117 group compared to placebo (P = 029), during LAR. CSJ117 also significantly reduced fractional exhaled nitric oxide before AIC at day 83; and significantly reduced the allergen-induced increase in % sputum eosinophil count [84]. This study demonstrates the potential of inhaled biologics, particularly those targeting the alarmin cytokines in the treatment and prevention of eosinophilic asthma. Aerosol CSJ117 by acting topically and blocking the immunopathological effects of TSLP may become the precise asthmatic drug delivery in the nearby future.
Eosinophilic asthma is principally a Th2-mediated airway disease. Th2 lymphocytes, ILCs, mast cells, and eosinophils secrete inflammatory cytokines, such as IL-4, IL-13, and IL-5 which promote airway inflammation, AHR, and remodeling. Additionally, dysfunctional epithelial cells exude alarmin cytokines, including IL-25, IL-33, and TSLP which further amplifies the inflammatory cascade, and airway remodeling. Patients with eosinophilic asthma respond favorably to targeted mAb, such as omalizumab, mepolizumab, dupilumab, and tezepelumab. However, biologics do not modify progressive airway remodeling which is responsible for severe asthma. Conventionally, asthma is best treated with locally-acting aerosol inhalers, such as LABA, ICS, and single triple inhaler therapy. Currently, there are no aerosol biologics for the treatment of asthma. CSJ117 is a potent neutralizing antibody Fab fragment against TSLP, formulated as a PulmoSol TM engineered powder, and is delivered to the lungs by a dry powder inhaler. CSJ117 delivered as an inhaler has been shown to attenuate the late asthmatic response, and the early asthmatic response after allergen inhalation challenge at day 84 of the treatment. CSJ11 significantly improved pre-AIC lung function (FEV1) compared to placebo. Additionally, CSJ117 significantly decreased inflammatory biomarkers of eosinophilic asthma, such as allergen-induced increase in % sputum eosinophil count, and FeNO. Pulmonary delivery of aerosol biologics to the lungs is a precise targeted route of drug administration to treat patients with eosinophilic asthma.
The author declares that the publication was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
AAER : Annualized asthma exacerbation rates
AATP : Alpha-1 anti-trypsin deficiency
ACQ-6 : Asthma Control Questionnaire-6
AHR :Airway hyperresponsiveness
AIC : Allergen inhalation challenge
ALI : Acute lung injury
AQLQ : Asthma Quality of Life Questionnaire
ARDS : Acute respiratory distress syndrome
BOOP : Bronchiolitis obliterans organizing pneumonia
COPD : Chronic obstructive pulmonary disease
COVID-19: Coronavirus Disease 19
CRSwNP: Chronic rhinosinusitis with nasal polyps
Dae : Aerodynamic diameter
DPI : Dry powder inhaler
AER : Early asthmatic response
EMT : Epithelial-mesenchymal transition
FeNO : Fractional exhaled nitric oxide
FEV1 : forced expired volume in one second
HLQoL : Health-related quality of life
ICS : Inhaled Corticosteroid
IgE : Immunoglobulin E
IL : Interleukin
ILCs : Innate type 2 lymphoid cells
LABA : Long-acting beta-2 agonist
LAR : Late asthmatic response
mAb : monoclonal antibody
OCS : Oral Corticosteroid
PAP : Pulmonary alveolar proteinosis
PMDI : Pressure metered dose inhaler
RSV : Respiratory syncytial virus
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2
SNOT-22: SinoNasal Outcome Test 22
Th2 : T helper type 2 lymphocytes
TNF-α : Tumor necrosis factor-α
TSLP : thymic stromal lymphopoietin
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I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.
Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”
Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner
My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.
My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.
Dear Agrippa Hilda- Editorial Coordinator of Journal of Neuroscience and Neurological Surgery, "The peer review process was very quick and of high quality, which can also be seen in the articles in the journal. The collaboration with the editorial office was very good."
I would like to express my sincere gratitude for the support and efficiency provided by the editorial office throughout the publication process of my article, “Delayed Vulvar Metastases from Rectal Carcinoma: A Case Report.” I greatly appreciate the assistance and guidance I received from your team, which made the entire process smooth and efficient. The peer review process was thorough and constructive, contributing to the overall quality of the final article. I am very grateful for the high level of professionalism and commitment shown by the editorial staff, and I look forward to maintaining a long-term collaboration with the International Journal of Clinical Case Reports and Reviews.
To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.
"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".
I thank the ‘Journal of Clinical Research and Reports’ for accepting this article for publication. This is a rigorously peer reviewed journal which is on all major global scientific data bases. I note the review process was prompt, thorough and professionally critical. It gave us an insight into a number of important scientific/statistical issues. The review prompted us to review the relevant literature again and look at the limitations of the study. The peer reviewers were open, clear in the instructions and the editorial team was very prompt in their communication. This journal certainly publishes quality research articles. I would recommend the journal for any future publications.
Dear Jessica Magne, with gratitude for the joint work. Fast process of receiving and processing the submitted scientific materials in “Clinical Cardiology and Cardiovascular Interventions”. High level of competence of the editors with clear and correct recommendations and ideas for enriching the article.
We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.
